Nanoparticles in general are known to improve drug pay-load and facilitate targeted drug delivery. In this context, chitosan-based (CS) nanoparticles have been shown to be useful as imaging and therapeutic drug/gene delivery systems. It is, however, difficult to synthesize nanoparticles with a narrow size distribution, particularly if the nanoparticles are formed from a naturally-occurring polymer like chitosan that has a wide molecular weight distribution. It is thought to be even more challenging to obtain buffer stable CS nanoparticles with suitable surface functional groups. For one, wide applications of CS nanoparticles are limited because of their poor stability at neutral or basic pH, including physiological conditions (pH 7.4). CS nanoparticles tend to agglomerate in phosphate buffer saline solution, which resembles physiological conditions. This agglomeration is a major hindrance for potential use of CS nanoparticles in biomedical applications. Several attempts have been made to improve the solubility and stability of CS nanoparticles, including modifying and/or derivatizing CS polymer chains using water soluble linkages, degrading high molecular weight CS polymers to low molecular weight polymer, or co-polymerization. However, these methods typically include multiple steps, are time consuming and laborious, and generally lead to new chemical moieties with altogether new properties.